Oligodendroglial macroautophagy is essential for myelin sheath turnover to prevent neurodegeneration and death.

Although macroautophagy deficits are implicated across adult-onset neurodegenerative diseases, we understand little about how the discrete, highly evolved cell types of the central nervous system use macroautophagy to maintain homeostasis. One such cell type is the oligodendrocyte, whose myelin sheaths are central for the reliable conduction of action potentials. Using an integrated approach of mouse genetics, live cell imaging, electron microscopy, and biochemistry, we show that mature oligodendrocytes require macroautophagy to degrade cell autonomously their myelin by consolidating cytosolic and transmembrane myelin proteins into an amphisome intermediate prior to degradation. We find that disruption of autophagic myelin turnover leads to changes in myelin sheath structure, ultimately impairing neural function and culminating in an adult-onset progressive motor decline, neurodegeneration, and death. Our model indicates that the continuous and cell-autonomous maintenance of the myelin sheath through macroautophagy is essential, shedding insight into how macroautophagy dysregulation might contribute to neurodegenerative disease pathophysiology. [Display omitted] • Oligodendrocytes (OLGs) use macroautophagy to maintain myelin sheaths • OLGs consolidate cytosolic cargo via Alfy-mediated selective autophagy • Disruption of OLG macroautophagy produces cell-autonomous myelin abnormalities • With age, OLG macroautophagy disruption leads to neurodegeneration and death Oligodendrocytes assemble myelin and support the axons they myelinate. Aber et al. report that oligodendrocytes coordinate autophagy and endocytosis to turn over myelin. The absence of oligodendroglial autophagy causes myelin abnormalities, behavioral dysfunction, glial and neurodegeneration, and death, demonstrating the importance of this process for a healthy CNS. [ABSTRACT FROM AUTHOR]